Brain-rejuvenating factor TIMP2 is associated with brain health and neuroprotective lifestyle in aged subjects

BackgroundTissue inhibitor of metalloproteinases 2 (TIMP2) has been shown to revitalize aspects of synaptic plasticity and hippocampus-dependent cognition in aged mice. We examined TIMP2s relevance in human brain aging and tested whether TIMP2 may be modifiable via known pro-plasticity behaviors in humans and mice. MethodsPlasma TIMP2 levels were quantified via SomaScan in three independent human cohorts, including two cross-sectional (UCSF: n=83; Stanford: n=31) and one with longitudinal measurement (ROSMAP: n=213). We examined associations of plasma TIMP2 with cognitive performance, brain volumes, and engagement in neuroprotective lifestyle behaviors, including objectively measured physical activity (UCSF) and a multi-domain lifestyle composite (ROSMAP). We used mouse models to directly test effects of environmental enrichment on (1) plasma TIMP2 levels and (2) hippocampal neurogenesis in wildtype versus TIMP2 knockout mice. ResultsHigher plasma TIMP2 associated with better global cognition and larger brain volumes across human cohorts. Longitudinal decreases in plasma TIMP2 associated with steeper cognitive decline. Physical activity positively associated with plasma TIMP2 cross-sectionally, and longitudinal changes in multi-domain lifestyle factors positively associated with change in TIMP2 levels over time in humans. Mice exposed to an enriched environment for 3 weeks exhibited elevated plasma TIMP2 levels. While wildtype mice exposed to enrichment exhibited elevated adult hippocampal neurogenesis, this effect was lost in mice in which TIMP2 had been deleted. ConclusionsTIMP2 demonstrates clinical relevance for brain aging in humans and may represent a mechanism through which lifestyle behaviors confer neuroprotection. Further examination of TIMP2 as a potential therapeutic target for prevention of cognitive decline is warranted.